Deoxynivalenol upregulates hypoxia-inducible factor-1α to promote an "immune evasion" process by activating STAT3 signaling.
Deoxynivalenol upregulates hypoxia-inducible factor-1α to promote an "immune evasion" process by activating STAT3 signaling.
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DOI：
10.1016/j.fct.2023.113975
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发表时间：
2023-07
期刊：
影响因子：
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通讯作者：
Luying Zhang;Xu Wang;E. Nepovimova;Qinghua Wu;Wenda Wu;K. Kuča
中科院分区：
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作者：
Luying Zhang;Xu Wang;E. Nepovimova;Qinghua Wu;Wenda Wu;K. Kuča
三氯乙烯霉菌毒素脱氧雪腐镰刀菌烯醇(DON)通过破坏宿主免疫系统，损害机体健康，对免疫反应产生负性调节作用。我们推测DON可以启动类似于免疫逃避的主动免疫抑制机制，改变细胞微环境，逃避免疫监视。我们使用RAW264.7巨噬细胞模型验证了这一假设。DON使免疫检查点PD-1和PD-L1、炎性细胞因子转化生长因子β和关键免疫逃避因子STAT3、VEGF4的表达迅速增加，并导致细胞缺氧。重要的是，缺氧诱导因子-1α(HIF-1α)是DON诱导免疫抑制的关键调节因子。经DON处理后，HIF-1α在胞浆内积聚，并逐渐向胞核转移。此外，DON通过STAT3信号通路激活HIF-1α，上调包括PD-1/PD-L1在内的下游信号。在DON作用下，STAT3/HIF-1α轴上调免疫抑制基因miR210-3p、LncRNAPVT1、LncRNAH19和LncRNAHOTAIR。此外，DON破坏线粒体功能，导致有丝分裂，并抑制免疫防御。总之，DON通过STAT3信号通路触发RAW264.7细胞内缺氧，迅速激活HIF-1α，激活免疫逃避信号、miRNAs和lncRNA，从而启动免疫逃避的关键环节。本研究为准确防治真菌毒素引起的免疫性疾病提供了进一步的线索。
Trichothecene mycotoxin deoxynivalenol (DON) negatively regulates immune response by damaging host immune system and harming the organism’s health. We hypothesized that DON can initiate an active immunosuppressive mechanism similar to "immune evasion" to alter the cellular microenvironment and evade immune surveillance. We tested this hypothesis using the RAW264.7 macrophage model. DON rapidly increased the expression of immune checkpoints PD-1 and PD-L1, inflammatory cytokine TGF-β, and key immune evasion factors STAT3, VEGF, and TLR-4, and caused cellular hypoxia. Importantly, hypoxia-inducible factor-1α (HIF-1α) acts as a key regulator of DON-induced immunosuppression. HIF-1α accumulated in the cytoplasm and was gradually transferred to the nucleus following DON treatment. Moreover, DON activated HIF-1α through STAT3 signaling to upregulate downstream signaling, including PD-1/PD-L1. Under DON treatment, immunosuppressive miR-210-3p, lncRNA PVT1, lncRNA H19, and lncRNA HOTAIR were upregulated by the STAT3/HIF-1α axis. Moreover, DON damaged mitochondrial function, causing mitophagy, and suppressed immune defenses. Collectively, DON triggered RAW264.7 intracellular hypoxia and rapidly activated HIF-1α via STAT3 signaling, activating immune evasion signals, miRNAs, and lncRNAs, thereby initiating the key link of immune evasion. This study offers further clues for accurate prevention and treatment of immune diseases caused by mycotoxins.